Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Ni].[C].[Pd]>[CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCC1CC=C(c2cc(F)cc(F)c2)CC1
Agent: [Ni]
Agent: [Pd]
Product: CCCCCC1CCC(c2cc(F)cc(F)c2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
Mixture of (4-pentyl-1-cyclohexenyl)-3,5-difluorobenzene (89 mmol), Raney nickel (3.5 g), and 500 ml of Solmix was subjected to a hydrogenation reaction at room temperature under normal pressure for 10 hours. At the time when the amount of hydrogen has come not to further reduce and the reaction has come not to progress, catalyst was changed from Raney nickel to palladium carbon (2.4 g), and stirred for 8 hours. Palladium carbon was filtered off and the solvent was distilled off. The residue was purified by column chromatography (eluent: heptane) to give a (4-pentyl-cyclohexyl)-3,5-difluorobenzene (81 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[CH3:20][S:21]([NH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl 4-amino-benzoate (5 g, 30 mmol, 1.0 equiv) was mixed in 50 mL of CH2Cl2 with Et3N (6.1 g, 60 mmol, 2.0 equiv). The solution was cooled to 0° C. and methanesulfonyl chloride (3.8 g, 33 mmol. 1.1 equiv) was added as a solution in 15 mL of CH2Cl2 dropwise over a 15 min period. The reaction was stirred for 4 h at which time it was diluted with 50 mL of water. Layers were separated and the organic layer was washed with 50 mL of saturated sodium bicarbonate solution and concentrated. The resulting ester was dissolved in 50 mL of MeOH and treated with 50 mL of 5 N NaOH for 4 h. The reaction solution was extracted with Et2O and the aqueous layer was acidified to give a white precipitate that was collected by filtration. The solid was dried and used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)[S:3]1.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C=O)C>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:14](=[O:16])[C:13]2[CH:17]=[C:9]([CH:8]=[C:4]3[S:3][C:2](=[O:1])[NH:6][C:5]3=[O:7])[CH:10]=[CH:11][C:12]=2[O:18][CH3:19])=[CH:24][CH:23]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(C=C2SC(=O)NC2=O)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 83.9 %

Procedure:
To a solution of 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoic acid (1.00 g) and 4-trifluoromethylbenzylamine (627 mg) in DMF (10 ml), diethyl cyanophosphate (615 mg) and triethylamine (370 mg) were added at room temperature in an argon atmosphere under stirring, and the mixture was stirred for 5 hours as it was. The reaction liquor was poured into ice water and the crystals deposited were collected by filtration, washed with water, and then dried to obtain 1.31 g (84%) of aimed compound as crystals. Further, these were recrystallized from ethanol to obtain purified aimed compound as yellow prismatic crystals. Melting point 210.0~211.5° C.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([CH2:81][SH:82])=[CH:77][CH:76]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=[C:2]([S:82][CH2:81][C:78]2[CH:79]=[CH:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (22.33 g, 62.01 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (16.03 g, 124.04 mmol). Then Pd2(dba)3 (2.84 g, 3.10 mmol) followed by Xantphos (3.59 g, 6.20 mmol) and 4-methoxy-α-toluenethiol (10.27 g, 65.11 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 24.35 g, 90.6% yield). 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.25 (m, 6H), 6.85 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH:1]12C[CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([CH:10]([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12])=O.C12CCC(C=C1)CC2[CH:25]=[O:26].O1CCC[CH2:28]1>>[CH:2]12[CH2:1][CH2:6][CH:5]([CH:4]=[CH:3]1)[CH2:28][CH:8]2[C:10]([CH2:25][OH:26])([C:14]([OH:16])=[O:15])[C:11]([OH:13])=[O:12]
Reactant: C1CCOC1
Reactant: O=C(O)C(C(=O)O)C(=O)C1CC2C=CC1C2
Reactant: O=CC1CC2C=CC1CC2
Product: O=C(O)C(CO)(C(=O)O)C1CC2C=CC1CC2
Reaction time: 1 h
Yield: 120.8 %

Procedure:
To a solution containing sodium malonate (17.0 g) of Example 7 in dry tetrahydrofuran (100 g), bicyclo[2,2,2]oct-5-ene-2-carboxaldehyde (13.6 g) obtained in Preparation Example 5 is slowly added, and the reaction is carried out at −20° C. in a nitrogen atmosphere for 1 hour, and then at 50° C. for 10 hours. Then, the reaction mixture is worked up as in the procedure of Example 1, to obtain 22 g of the pure title compound (purity: 99%, yield: 92%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]([CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:18][CH2:17]2)#[N:13].[H-].[Na+].[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:64]=[CH:63][C:62]([C:65](=O)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:61][CH:60]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:46]([O:50][C:51]([N:53]1[CH2:57][CH2:56][C@H:55]([O:58][C:59]2[CH:60]=[CH:61][C:62]([C:65](=[CH:24][CH:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[C:14]([C:12]#[N:13])[CH:15]=4)[CH2:20]3)[C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:63][CH:64]=2)[CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCOC(=O)C(=O)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: N#Cc1ccc2c(c1)CCC(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CC1CCc2cc(C#N)ccc2C1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
9.0 g of (6-cyano-1,2,3,4-tetrahydro-2-naphthyl)methyltriphenylphosphonium p-toluenesulfonate was suspended in 150 ml of tetrahydrofuran, followed by gradual addition of 600 mg of 60% sodium hydride. The thus prepared mixture was refluxed under heating for 20 minutes. After cooling down to room temperature, to the resulting reaction solution was added 10 ml of a tetrahydrofuran solution containing 4.16 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-2-oxoacetate. The resulting reaction mixture was stirred for 10 minutes, and then refluxed under heating for 2 hours. After cooling down to room temperature, the reaction product thus obtained was dissolved in ethyl acetate, and washed with water and saturated sodium chloride aqueous solution in that order. After drying the resulting organic layer to distill off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent, thereby obtaining 3.90 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]3-(6-cyano-1,2,3,4-tetrahydro-2-naphthyl)acrylate in a yellow oily form as a mixture of E and Z forms. 2.58 g of the thus obtained E/Z mixture was dissolved in 40 ml of ethanol, and the resulting solution was mixed with 650 mg of palladium oxide.1H2O.barium sulfate, and then subjected to catalytic hydrogenation under normal pressure for 5 hours. After removing the catalyst by filtration and distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/ethyl acetate mixture as an elution solvent. In this way, 1.69 g of the title compound was obtained in a yellow oily form.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH2:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 6-chloro-9H-purin-2-amine (5.0 g, 29.6 mmol) and NaH (1.43 g, 32.5 mmol) in DMF (30 mL) was stirred at room temperature for 0.5 h. (2-(Chloromethoxy)ethyl)trimethylsilane (SEMCl, CAS Reg. No. 76513-69-4, 4.91 g, 29.6 mmol) was added and the resulting mixture was stirred at room temperature for 1.0 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 3:1 petroleum ether/ethyl acetate to afford 117a (5.1 g, 58%) as a yellow solid. MS-ESI: [M+H]+ 300.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23]O)=[CH:14]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:23][CH2:22][C:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[NH:13][CH:14]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: OCCc1c[nH]c2ccccc12
Product: Cc1cc(C)n2nc(SCCc3c[nH]c4ccccc34)nc2n1
Yield: 54 %

Procedure:
The title compound was prepared according to the experimentals described for Example 9 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 2-(1H-indol-3-yl)ethanol in 54% yield; EM (calc.): 323.1; MS (ESI) m/e: 324.1 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 39.2 g of alpha-bromo-p-tolunitrile in 1 L of acetone are added sequentially 20.72 g of 1,2,4-triazole, 27.8 g of potassium carbonate and 1.7 g of potassium iodide. The reaction is stirred for 8 hours at 55° under argon, cooled to room temperature, filtered and evaporated. The residue is partitioned between methylene chloride and water. The organic phase is separated, washed with brine, dried over sodium sulfate and evaporated. The resulting crystalline crude product is chromatographed on 300 g of silica with toluene and ethyl acetate (1:1 to 0:1) to yield 4-[1-(1,2,4-triazolyl)methyl]benzonitrile (see example 9).
Reaction SMILES: C([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])([CH2:14][O:15]CC2C=CC=CC=2)[O:12][C@@H:11]([N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])[C@@H:10]1[O:43][S:44]([C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)(=[O:46])=[O:45])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[C:50]1([CH3:53])[CH:51]=[CH:52][C:47]([S:44]([O:43][C@@H:10]2[C@H:9]([OH:8])[C@@:13]([CH2:23][O:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:26])=[O:27])([CH2:14][OH:15])[O:12][C@H:11]2[N:35]2[CH:42]=[CH:41][C:39](=[O:40])[NH:38][C:36]2=[O:37])(=[O:46])=[O:45])=[CH:48][CH:49]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@]2(CO)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Reaction time: 48 h
Yield: 51.5 %

Procedure:
To a solution of compound 75 (0.80 g, 1.0 mmol) in absolute ethanol (2 cm3) was added 20% palladium hydroxide over carbon (0.80 g) and the mixture was degassed several times with hydrogen and stirring was continued under hydrogen for 48 h. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 76A (0.30 g, 49%) as a white solid material. δH (CD3OD) 7.67 (4H, m), 7.45 (1H, d, J 8.2 Hz), 7.34 (4H, m), 5.86 (1H, d, J 8.0 Hz), 5.40 (1H, d, J 8.1Hz), 4.95 (1H, m), 4.35 (1H, d, J 5.0 Hz), 4.17 (2H, m), 3.61 (2H, s), 2.40 (6H, s). δc (CD3OD) 165.4, 151.6, 147.5, 146.6, 141.3, 134.0, 133.8, 131.4, 130.9, 129.2, 128.9, 103.7, 88.0, 85.4, 80.7, 72.4, 71.0, 64.3, 21.7, 21.6. FAB-MS m/z 583 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12][N:11]([C:14]3[C:19](C(O)=O)=[CH:18][N:17]=[C:16]4[NH:23][CH:24]=[CH:25][C:15]=34)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:26][NH2:27])[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[NH:23][CH:24]=[CH:25][C:15]=34)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc2[nH]ccc2c1N1CCC(CN2C(=O)c3ccccc3C2=O)(c2ccc(Cl)cc2)CC1
Solvent: O
Product: NCC1(c2ccc(Cl)cc2)CCN(c2ccnc3[nH]ccc23)CC1
Yield: 46.9 %

Procedure:
A mixture of crude 4-[4-(4-chlorophenyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl)-piperidin-1-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (12.8 mg, 0.025 mmol) and water (1 mL) was irradiated in a microwave reactor (250W) for 2 hrs at 180° C. The resulting suspension was filtered and the filtrate was concentrated. Preparative TLC gave the product (4 mg, 47%). LC-MS (LCT2) m/z 342 [M+H+], Rt 2.19 min.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[CH:9][CH:8]=1.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].O>CN(C)C=O>[CH2:35]([O:34][C:33]([N:16]([CH2:15][CH:14]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:37])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COCOc1ccc(CC(CNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N(CC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
A portion of 144 mg of 60% sodium hydride were suspended in 15 ml of dimethylformamide and cooled to 0° C., followed by dropwise addition of 1.34 g of N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzene sulfonamide, and then followed by addition of 391 mg of ethyl chlorocarbonate. After stirring at room temperature for four hours, the reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed in saturated aqueous sodium chloride and dried over magnesium sulfate, to distill off the solvent. The obtained residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methylene chloride was obtained 1.49 g of N-ethoxycarbonyl-N-[3-(4-methoxymethyloxyphenyl)-2-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([OH:24])=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:25])=[N:6][CH:7]=1.Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=3[O:24][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[N:28]=3)=[CH:10][C:9]=2[F:25])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Reactant: Nc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3Oc3ccnc(N)n3)cc2F)cn1
Temperature: 120 °C

Procedure:
To a 5 mL vial were added a stir bar, 4′-(5-aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol (40 mg, 0.12 mmol), 4-chloropyrimidin-2-amine (17.8 mg, 0.14 mmol), DMSO (1 mL) and Cs2CO3 (52 mg, 0.16 mmol). The vial was flushed with nitrogen and heated for 15 hours at 120° Celsius. The reaction was diluted with 5 mL of ethyl acetate and 5 mL of brine. The aqueous layer was then extracted with ethyl acetate (3×10 mL), the combined organic extracts dried over Na2SO4, and concentrated to dryness. The crude product was purified by HPLC to give the title compound. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (s, 1H), 8.09-8.07 (d, J=1.4, 1H), 8.07-8.05 (d, J=7.0, 1H), 7.96-7.88 (m, 1H), 7.82-7.74 (d, J=1.6, 2H), 7.71 (s, 1H), 7.41-7.37 (dd, J=8.1, 1.7, 1H), 7.37-7.32 (dd, J=12.4, 1.7, 1H), 6.64-6.56 (d, J=7.0, 1H).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:12]#[N:13])[C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([C:12]#[N:13])[C:9]([Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(C(=O)O)=C(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#CC(C(=O)Cl)=C(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
To 100 ml. of toluene solution containing 50 g. (0.2 mole) of β,β-diphenyl-α-cyanoacrylic acid, 30 g. (0.25 mole) of thionyl chloride is added and the solution is refluxed overnight. After cooling, yellow prisms are collected to give 49.5 g., 92% yield of product, m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9]N(C)C)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(O)(=O)C(O)=[O:19]>C(Cl)Cl.O>[Cl:13][C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][CH:9]=[O:19]
Reactant: O=C(O)C(=O)O
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: ClCCl
Solvent: O
Product: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (10 g, 38.3 mmol) was dissolved in methylene chloride (200 ml) and stirred with a solution of oxalic acid (14.5 g, 115 mmol) in water (80 ml) at room temperature for 18 hours. The layers were separated and the aqueous layer extracted with methylene chloride (50 ml). The combined organic layers were washed with water and brine, dried over magnesium sulfate and filtered. The solution was evaporated to yield the title compound. NMR (CDCl3) δ 9.70 (s, 1), 8.01 (s, 1), 7.49 (s, 1), 3.98 (s, 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10](C(O)=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16]([O-])(=O)C.[NH4+].C[N:22]([CH:24]=[O:25])C>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:16])=[CH:11][C:10]([C:24]([NH2:22])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccn(-c2cccc(Br)c2)n1
Reactant: CC(=O)[O-]
Reactant: CN(C)C=O
Agent: [NH4+]
Product: Cc1cc(C(N)=O)nn1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of the carboxylic acid (3.79 g, 14.1 mmol) in DMF (47 ml) was added 1,1-carbonyldiimidazole (3.45 g, 21.2 mmol) and the mixture was stirred at room temperature for 3 hours. Anhydrous ammonium acetate (10.9 g, 141 mmol) was then added and the reaction was stirred at room temperature for an additional 16 hours. The reaction mixture was partitioned between ethylacetate and saturated sodium bicarbonate. The organic phase was washed with water, brine, then dried over sodium sulfate and concentrated. The crude product obtained was purified by silica-gel column chromatography (2:3 hexanes/ethyl acetate) to give the product as a white solid (3.23 g, 82%).
Reaction SMILES: Cl[C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3].[CH3:10][OH:11]>>[CH3:10][O:11][C:2]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])=[O:3]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CO
Product: COC(=O)N1CCNC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.9 parts by weight of N-chlorocarbonyl-imidazolid-2-one were introduced into 70 parts by volume of ice-cold methanol and the mixture was stirred for 1 hour at room temperature and subsequently for 1 hour at 40°-50° C. After stripping off the excess methanol, the product was recrystallized from acetone.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]([CH2:13][O:14][CH3:15])OC.[OH-].[K+].BrC[CH2:20][CH:21]([CH3:28])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26]>C(O)C.CCCCCC>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:15]([O:14][CH:13]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:10][CH:25]([CH3:26])[CH2:24][CH2:23][CH:22]=[C:21]([CH3:28])[CH3:20])[CH2:28][CH:21]([CH3:20])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])=[CH:5][CH:4]=1)[CH3:2]
Reactant: COCCOC
Reactant: CCc1ccc(O)cc1
Reactant: CC(C)=CCCC(C)CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CCc1ccc(C(CC(C)CCC=C(C)C)OC(CC(C)CCC=C(C)C)c2ccc(CC)cc2)cc1

Procedure:
Into a 2 liter round-bottomed flask equipped with a cooling bath, stirrer and thermometer was placed 70 g. of p-ethylphenol and 400 ml dimethoxy ethane. The resulting solution was stirred and 30 g. of potassium hydroxide in 200 ml ethanol was added within 5 minutes. The temperature was maintained below 20° C during this addition and then 110 g. of 1-bromo-3,7-dimethyl-6-octene was added dropwise over 15 minutes. The reaction was stirred for two hours longer at 80° C and then allowed to rise to room temperature. After 3 hours the reaction was poured into a mixture of 500 g. of ice and 1 liter of hexane. The phases were separated and the aqueous layer was reextracted with two 0.5 l-portions hexane. All organic phases were combined and washed successively with 1.0 liter of water, two 250 ml portions of 2N sodium hydroxide and 1.0 liter of water. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo with water aspirator. The dark solution was chromatographed on 1 kg silica gel in hexane-ethylacetate (9:1 parts by volume). The fractions yielding p-ethyphenyl-3,7-dimethyl-6-octenyl ether were concentrated in a rotary evaporator at 40° C bath temperature using a water pump for the vacuum. The residue was distilled through a small Widmer column. The fraction of b.p. 118°-120° C 0.05 mmHg was p-ethylphenyl-3,7-dimethyl-6-octenyl ether.